Behavioral economic analysis of the effects of N-substituted benztropine analogs on cocaine self-administration in rats

Abstract

Rationale and objectives: Benztropine (BZT) analogs and other atypical dopamine uptake inhibitors selectively decrease cocaine self-administration at doses that do not affect responding maintained by other reinforcers. Those effects were further characterized in the current study using a behavioral economic assessment of how response requirement (price) affects reinforcers obtained (consumption) in rats.

Methods: Two groups of rats were trained to press levers with food (45-mg pellet) or cocaine (0.32 mg/kg/injection) reinforcement under fixed-ratio (FR) 5-response schedules. In selected sessions, the FR requirement was increased (5-80) during successive 20-min components to determine demand curves, which plot consumption against price. An exponential function was fitted to the data to derive the consumption at zero price (Q ₀) and the rate of decrease in consumption (essential value, EV) with increased price. The BZT analogs, AHN1-055, AHN2-005, JHW007 (3.2-10 or 17.8 mg/kg, each), vehicle, or comparison drugs (methylphenidate, ketamine), were administered i.p. before selected demand-curve determinations.

Results: Consumption of cocaine or food decreased with increased FR requirement. Each drug shifted the demand curve rightward at the lowest doses and leftward/downward at higher doses. The effects on EV and Q ₀ were greater for cocaine than for food-reinforced responding. Additionally, the effects of the BZT analogs on EV and Q ₀ were greater than those obtained with a standard dopamine transport inhibitor, methylphenidate, and the NMDA antagonist, ketamine (1.0-10.0 mg/kg, each). With these latter drugs, the demand-curve parameters were affected similarly with cocaine and food-maintained responding.

Conclusions: The current findings, obtained using a behavioral economic assessment, suggest that BZT analogs selectively decrease the reinforcing effectiveness of cocaine.

Keywords: Behavioral economics; Benztropine analogs; Cocaine; Demand curves; Drug abuse; Essential value; Rats; Self-administration.